Cellular aging or cellular senescence is a universal attribute of normal non-transformed cells that is manifested by morphological changes accompanied by an age-dependent loss of proliferative potential, including the failure of the cells to respond to exogenous growth factors. A variety of theories have been proposed to explain the phenomenon of cellular senescence. Experimental evidence suggests that the age-dependent loss of proliferative potential may be the function of a genetic program (see, e.g., Smith et al. (1980) Mech. Age. Dev. 13:387; and Kirkwood et al. (1975) Theor. Biol. 53:481 ). This evidence includes cell fusion studies with human fibroblasts in vitro that demonstrate that the quiescent cellular senescent phenotype is dominant over the proliferative phenotype (see, e.g., Pereira-Smith et al. (1982) Somatic Cell Genet. 8:731; and Norwood et al. (1974)
Proc. Natl. Acad. Sci. USA 71:223) and that protein synthesis in senescent cells, prior to fusion with young cells, is required for the inhibition of DNA synthesis within the young nucleus of the heterodikaryon (see, e.g., Burmer et al. (1983) Exp. Cell Res. 145:708; and Drescher-Lincoln et al. (1984) Exp. Cell Res. 153:208). Also, microinjection of senescent fibroblast mRNA into young fibroblasts inhibits the ability of the young cell to synthesize DNA (see, e.g., Lumpkin et al. (1986) Science 232:393) and entry of the young cell into the S phase of the cell cycle (Lumpkin et al. (1985) Exp. Cell Res. 160:544). Further, unique mRNA species are amplified in senescent fibroblasts in vitro (see, e.g., Wellinger et al. (1986) J. Cell Biol. 34:203; Flemming et el. (1988) Proc. Natl. Acad. Sci. USA 85:4099; West et al. (1989) Exp. Cell Res. 184:138; and Giordano (1989) Exp. Cell Res. 185:399). It has also been suggested that an altered genetic program exists in senescent human fibroblasts, which involves the repression of c-fos expression at the transcriptional level (see, e.g., Seshadri et al. (1990) Science 247:205). Thus, there appear to be genotypic, as well as phenotypic differences between young and old cells.